Calcium phosphate cements made from (TTCP) with surface whiskers and process for preparing same

ABSTRACT

A tetracalcium phosphate (TTCP) particle for use in preparing a fast-setting, bioresorbable calcium phosphate cement is disclosed. The TTCP particle has a basic calcium phosphate whiskers on a surface thereof; the basic calcium phosphate whiskers having a Ca/P molar ratio greater than 1.33, and having a length up to about 5000 nm and a width up to about 500 nm. The basic calcium phosphate whiskers are substantially free of a hydroxyapatite phase and mainly composed of TTCP phase.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part application of U.S. patent application Ser. No. 10/607,023, filed Jun. 27, 2003, which is a continuation-in-part application of U.S. patent application Ser. No. 10/414,582, filed Apr. 16, 2003, which is a continuation-in-part application of U.S. patent application Ser. No. 09/615,384, filed Jul. 13, 2000, now abandoned, which is a continuation-in-part application of U.S. patent application Ser. No. 09/351,912, filed Jul. 14, 1999, now U.S. Pat. No. 6,379,453B1. The above-listed applications are commonly assigned with the present invention and the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a tetracalcium phosphate (TTCP) for producing fast-setting, bioresorbable calcium phosphate cements (CPC), and in particular, to a tetracalcium phosphate having whiskers on the surface thereof for producing fast-setting, bioresorbable CPC having a high initial strength.

2. Description of the Related Art

U.S. Pat. No. 6,379,453B1 which is commonly assigned with the present invention discloses a process for producing a fast-setting, bioresorbable calcium phosphate cement comprising the following steps: obtaining a powder mixture from at least one calcium phosphate selected from the group consisting of Ca₄(PO₄)₂O, Ca(HPO₄)₂H₂O, CaHPO₄, Ca₈H₂(PO₄)₆.5H₂O, α-Ca₃(PO4)₂, β-Ca₃(PO₄)₂, Ca₂P₂O₇, Ca₂H₂P₂O₈, wherein the molar ratio of Ca to P in the mixture is roughly between 1 and 2; mixing the powder mixture in a phosphate-containing solution to obtain a powder/solution mixture having a concentration of less than 4 g powder mixture per ml solution; immediately heating the powder/solution mixture to a temperature of roughly 50° C.-350° C. to obtain a powder containing uniformly distributed submicron-sized apatite crystals; and mixing the apatite crystal-containing powder in a phosphate ion-containing solution to obtain a fast-setting, bioresorbable calcium phosphate cement.

SUMMARY OF THE INVENTION

An extensive study on the preparation of the fast-setting, bioresorbable calcium phosphate cement disclosed in U.S. Pat. No. 6,379,453B1 has been conducted by the same inventors and their co-workers, and found that a fast-setting, bioresorbable CPC having a high initial strength can be prepared from a unique calcium phosphate, tetracalcium phosphate (Ca₄(PO₄)₂O, TTCP) particle having basic whiskers or fine crystals on the surface thereof, wherein said basic whiskers or fine crystals have a Ca/P ratio greater than 1.33. Therefore an object of the invention is to provide such a unique TTCP particle. Another object of the present invention is to provide a process for preparing said unique TTCP particle. A further object of the present invention is to provide a fast-setting, bioresorbable CPC calcium phosphate cement prepared from said unique TTCP particle.

The invention accomplishes the above object by providing a tetracalcium phosphate (Ca₄(PO₄)₂O, TTCP) particle having basic calcium phosphate whiskers on a surface of said TTCP particle; said basic calcium phosphate whiskers having a length up to about 5000 nm and a width up to about 500 urn, and preferably, a length from about 1 nm to about 2000 nm and a width from about 1 nm to about 200 rim. Said basic calcium phosphate whiskers have a Ca/P molar ratio greater than 1.33, and preferably greater than 1.35 and less than 4.0. Said basic calcium phosphate whiskers have a non-stoichiometric chemical composition. Further, said basic calcium phosphate whiskers are substantially free of a hydroxyapatite phase, and comprises TTCP as a major phase.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS 1A to 1C are related to microstructure and diffraction pattern of calcium phosphate whiskers grown on TTCP surface according to the present invention, wherein (a) bright field image of whiskers; (b) electron diffraction pattern of whiskers; and (c) interpretation of the diffraction pattern.

FIG. 2 shows XRD patterns, wherein (a) TTCP without whisker treatment; (b) TTCP with whisker treatment in (NH₄)₂HPO₄ for 5 minutes; and (c) CPC prepared from whisker-treated TTCP powder immersed in Hanks' solution for 24 hours.

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses a process for preparing a tetracalcium phosphate (TTCP) powder comprising TTCP particles comprising basic calcium phosphate whiskers on surfaces of said TTCP particles, said process comprising the following steps:

a) mixing a TTCP powder with a whisker-inducing solution so that basic calcium phosphate whiskers start to grow on surfaces of TTCP particles of said TTCP powder;

b) terminating the growth of said calcium phosphate whiskers by drying the whisker-inducing solution in the mixture, so that said calcium phosphate whiskers have a length up to about 5000 nm and a width up to about 500 nm, and preferably, a length from about 1 nm to about 2000 nm and a width from about 1 nm to about 200 nm, said basic calcium phosphate whiskers have a Ca/P molar ratio greater than 1.33, preferably greater than 1.35 and less than 4.0, and said basic calcium phosphate whiskers have a non-stoichiometric chemical composition, preferably said basic calcium phosphate whiskers are substantially free of a hydroxyapatite phase, and comprises TTCP as a major phase.

Optionally, at least one additive selected from the group consisting of sodium phosphate (Na₃PO₄), disodium hydrogen phosphate (Na₂HPO₄), sodium dihydrogen phosphate (NaH₂PO₄), disodium hydrogen phosphate dodecahydrate (Na₂HPO₄.12H₂O), disodium hydrogen phosphate heptahydrate (Na₂HPO₄.7H₂0), sodium phosphate dodecahydrate (Na₃PO4.12H₂O), orthophosphoric acid (H₃PO₄), calcium sulfate (CaSO₄), Ca₄(PO₄)₂O, CaHPO₄.2H₂O, CaHPO₄, Ca₈H₂(PO₄)₆.5H₂ _(O), alpha-Ca₃(PO₄)₂, beta-Ca₃(PO₄)₂, Ca₂P₂O₇, and Ca₂H₂P₂O₈, (NH₄)₃PO₄, (NH₄)₂HPO₄, and (NH₄)H₂PO₄ together with said TTCP particles are mixed with the whisker-inducing solution in step a).

Optionally, said drying in step b) is carried out by heating the mixture resulting from step a) at a temperature less than about 1000° C. Preferably, said drying in step b) comprises separating the mixture resulting from step a) and heating the separated powder at a temperature of about 50 to 500° C.

The heating includes (but not limited to) the conventional oven/furnace heating, resistance heating, infrared heating, microwave heating, electron beam heating, ion beam heating, laser beam heating and plasma heating. Preferably said heating is conducted in vacuum, inert atmosphere or air atmosphere.

The whisker-inducing solution in step a) may be an acidic aqueous solution, a basic aqueous solution, an organic solvent or a substantially pure water. The acidic aqueous solution may contain at least one Ca or P source, or is free from Ca and P. The acidic aqueous solution can be selected from the group consisting of nitric acid (HNO₃), hydrochloric acid (HCl), phosphoric acid (H₃PO₄), carbonic acid (H₂CO₃), sodium dihydrogen phosphate (NaH₂PO₄), sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, potassium dihydrogen phosphate (KH₂PO₄), ammonium dihydrogen phosphate (NH₄H₂PO₄), malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, oxalic acid and their mixture.

The basic aqueous solution for use as the whisker-inducing solution in the method of the present invention may contain at least one Ca or P source, or is substantially free from Ca and P. The basic aqueous solution may be selected from the group consisting of ammonia, ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide, disodium hydrogen phosphate (Na₂HPO₄), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na₃PO₄.12H₂O), dipotassium hydrogen phosphate (K₂HPO₄), potassium phosphate tribasic (K₃PO₄), diammonium hydrogen phosphate ((NH₄)₂HPO₄), ammonium phosphate trihydrate ((NH₄)₃PO₄.3H₂O), sodium bicarbonate (NaHCO₃), and their mixture.

Preferably, said whisker-inducing solution in step a) is a basic aqueous solution. More preferably, said basic aqueous solution is a diammonium hydrogen phosphate ((NH₄)₂HPO₄), Na₂HPO₄, or K₂HPO₄ aqueous solution. A suitable diammonium hydrogen phosphate ((NH₄)₂HPO₄) aqueous solution has a concentration of at least 5 wt %, preferably 10-60 wt %, based on the weight of said solution, and the mixing of said TTCP powder with this diammonium hydrogen phosphate ((NH₄)₂HPO₄) aqueous solution in step a) is in a ratio of less than about 10 g powder per ml solution, preferably less than about 5 g powder per ml solution. In one of the preferred embodiment of the present invention, said concentration is about 33 wt %, and the mixing ratio is about 1 gm TTCP per 13 ml solution.

The present invention also discloses a calcium phosphate cement (CPC) powder comprising the TTCP powder of the present invention.

The following examples are intended to demonstrate the invention more fully without acting as a limitation upon its scope, since numerous modifications and variations will be apparent to those skilled in this art.

TTCP Preparation

The TTCP powder was fabricated in-house from the reaction of dicalcium pyrophosphate (Ca₂P₂O₇) (Sigma Chem. Co., St. Louis, Mo., USA) and calcium carbonate (CaCO₃) (Katayama Chem. Co., Tokyo, Japan) using the method suggested by Brown and Epstein [Journal of Research of the National Bureau of Standards—A Physics and Chemistry 6 (1965) 69A 12].

TEM Examination

A Hitachi Model-HF2000 200 kV field emission transmission electron microscope (TEM) equipped with a Noran Vayager Model 1000 energy dispersive spectroscopy (EDS) system was used for the study. The aperture size for microchemical analysis (Ca/P ratio) is 15 nm.

EXAMPLE 1 Whisker-Inducing Treatment of TTCP Particles Treated in Phosphate-Containing Basic Solution

Ca₄(PO₄)₂O (TTCP) powder as synthesized was sieved with a #325 mesh. The sieved powder has an average particle size of about 10 gin. An aqueous solution of diammonium hydrogen phosphate was prepared by dissolving 20 g of diammonium hydrogen phosphate, (NH4)2HPO4, in 40 ml deionized water. The resulting solution had a pH value of 8.02. To the TTCP powder the basic aqueous solution of diammonium hydrogen phosphate was added according to the ratio of 1 gm TTCP/13 ml solution. The TTCP powder was immersed in the basic aqueous solution for various periods of time of 1 minute, 5 minutes and 10 minutes, and filtered rapidly with a vacuum pump. again. The resulting powder cake was dried in an oven at 50° C. The dried powder was dispersed in ethanol with supersonication. A drop of the dispersion was dripped on a single-side carbon sieve of #325 mesh having a diameter of 3 mm, and left dry to obtain a specimen coated with a thin carbon film for electrical conductivity for TEM examination. The microchemical analysis (Ca/P ratio) results of ten specimens (P1 to P10) for each treat time are shown in Table 1. TABLE 1 Whisker Whisker Treat Ca/P width width time P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 Avg. SD* (nm) (nm) 1 min 1.20 1.30 1.26 1.14 1.12 1.03 1.22 1.19 1.14 1.25 1.19 0.08 <50 <100 5 min 1.85 1.61 1.35 1.76 1.40 1.52 1.63 1.53 1.35 1.38 1.54 0.17 <100 <300 10 min  3.81 3.20 1.78 1.74 1.80 1.38 1.61 1.81 2.01 1.63 2.08 0.78 <100 <300 *SD = standard deviation *SD = standard deviation

FIG. 1 represents a typical microstructure of the calcium phosphate whiskers grown on TTCP surface under such condition. FIG. 1A is a bright-field imag_(e) showing the whiskers are substantially radial-oriented and the majority of which have lengths <300 urn and widths <100 nm; FIG. 1B is a typical electron diffraction pattern of such whiskers. The dotted-ring pattern is a direct result of the diffraction of numerous nano-sized whiskers; FIG. 1C is the indexing/interpretation of the diffraction pattern, which clearly shows that every ring matches a certain crystallographic plane of TTCP phase, indicating the whiskers have a TTCP crystal structure. The absence of hydroxyapatite (HA) phase (100) ring (d=0.817 nm) in the diffraction pattern excludes the possibility for the whiskers to have an apatite crystal structure under this whisker treatment condition. It also can be seen from Table 1 that basic calcium phosphate whiskers have a Ca/P ratio other than 1.67, i.e. a non-stoichiometric chemical composition. The Ca?P ratio ofhydroxyapatite (HA) is 1.67. The results show that Ca/P ratio is sensitive to the process condition (in this case, treating time).

EXAMPLE 2 Whisker-Inducing Treatment of TTCP Particles Treated in Phosphate-Containing Acidic Solution

The procedures of Example I were repeated except that the basic aqueous solution was changed to 1M phosphorus acid aqueous solution having a pH of 0.8 and the immersion time was changed to 30 seconds. The results are shown in Table 2. TABLE 2 Whisker Whisker Treat Ca/P width length time P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 Avg SD* (nm) (nm) 30 sec 3.73 2.0 2.28 1.41 2.65 1.43 1.77 1.89 1.65 1.54 2.04 0.71 <200 <600 *SD = standard deviation

EXAMPLE 3 Whisker-Inducing Treatment of TTCP Particles Treated in Phosphate-Free Basic Solution

The procedures of Example 1 were repeated except that the basic aqueous solution was changed to a basic aqueous NaOH solution having a pH of 10.66 and the immersion time was changed to 30 seconds and 24 hours. For the specimens treated for 30 seconds no whisker was observed on TTCP surface. The results for the treat time of 24 hours are shown in Table 3. TABLE 3 Whisker Whisker Treat Ca/P width length time P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 Avg SD* (nm) (nm) 24 hr 1.90 2.19 2.80 3.40 1.47 2.05 1.53 1.63 1.42 2.03 2.04 0.63 <200 <600 *SD = standard deviation

EXAMPLE 4 Whisker-Inducing Treatment of TTCP Particles Treated in Phosphate-Free Acidic Solution

The procedures of Example 1 were repeated except that the basic aqueous solution was changed to 0.16M HCl aqueous solution having a pH of 0.8 and the immersion time was changed to 30 seconds, 10 minutes, one hour and 24 hours. For the specimens treated for 30 seconds no whisker was observed on TTCP surface. The results for the remaining treat times are shown in Table 4. TABLE 4 Whisker Whisker Treat Ca/P width width time P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 Avg. SD* (nm) (nm) 10 min 1.61 1.92 1.40 1.52 1.52 <50 <100  1 min 1.41 1.90 1.52 1.67 1.57 1.42 1.53 1.46 1.38 1.60 1.55 0.15 <100 <200 24 min 2.65 1.53 1.61 1.77 1.52 2.23 1.36 1.83 1.44 2.09 1.80 0.41 <200 <600 *SD = standard deviation

EXAMPLE 5 Compressive Strength of CPC Prepared from the Whisker-Grown TTCP Particles

Ca₄(PO₄)₂O (TTCP) powder as synthesized was sieved with a #325 mesh and has an average particle size of about 10 gm. To the sieved TTCP powder a HCl aqueous solution having a pH of 0.8 was added according to the ratio of 1 gm TTCP/13 ml solution. The sieved TTCP powder was immersed in the HCl solution for 12 hours, filtered rapidly and washed with deionized water, and filtered rapidly with a vacuum pump again. The resulting powder cake was dried in an oven at 50° C. The dried powder was divided into halves, ground for 20 minutes and 120 minutes separately, and combined. A setting solution of diammonium hydrogen phosphate was prepared by dissolving 20 g of diammonium hydrogen phosphate, (NH₄)₂HPO₄, in 40 ml deionized water. 100 g of the mixed ground powder and 35 ml of the setting solution were well mixed to form a paste, which was then filled in molds to form specimens for compression test. The specimens were removed from the molds 15 minutes after the mixing, and soaked in a Hanks' solution. The soaked specimens were removed from the Hanks' solution at various periods of soaking time, and were immediately subjected to the compression test without drying. The compression test was conducted according to a method commonly used in the literature. The cylindrical samples have a diameter of 6 mm and a length of 12 mm. Results: compressive strength is 27.4 MPa for the soaking time of 20 minutes, and 48 MPa for one-day soaking time.

EXAMPLE 6 Compressive Strength of CPC Prepared from the Whisker-Grown TTCP Particles

Ca₄(PO₄)₂O (TTCP) powder as synthesized was sieved with a #325 mesh and has an average particle size of about 10 gm. To the sieved TTCP powder the aqueous (NH₄)₂HPO₄ solution prepared in Example 1 was added according to the ratio of 1 gm TTCP/13 ml solution. The sieved TTCP powder was immersed in the (NH₄)₂HPO₄ solution for 5 minutes, filtered rapidly and washed with deionized water, and filtered rapidly with a vacuum pump again. The resulting powder cake was dried in an oven at 50° C. The dried powder was ground 120 minutes to obtain a powder A. The procedures in Example 5 were repeated to obtain a powder B except that the dried powder was ground ordy for a period of 300 minutes. A mixed powder of A and B in a ratio of 1:1 ratio was subjected to the compression tests following the procedures recited in Example 5. Results: compressive strength is 26 MPa for the soaking time of 20 minutes, and 42.8 MPa for one-day soaking time.

EXAMPLE 7 Compressive Strength of CPC Prepared from the Whisker-Grown TTCP Particles

The procedures in Example 5 were repeated except that the HCl solution was changed to the aqueous (NH₄)₂HPO₄ solution prepared in Example 1 and the soaking time was changed to 5 minutes. Results: compressive strength is 18.6 MPa for the soaking time of 20 minutes, and 48.8 MPa for one-day soaking time.

EXAMPLE 8 Compressive Strength of CPC Prepared from the Whisker-Grown TTCP Particles

Ca₄(PO₄)₂O (TTCP) powder as synthesized was sieved with a #325 mesh and ground for two hours. To the ground TTCP powder the powder B prepared in Example 5 was added and mixed in a ratio of 1:1. The resulting mixed powder was subjected to the compression tests following the procedures recited in Example 5. Results: compressive strength is 19.7 MPa for the soaking time of 20 minutes, and 43.6 MPa for one-day soaking time.

EXAMPLE 9 X-Ray Diffraction of Whisker-Treated TTCP Powder and Immersed CPC Prepared from Such TTCP

A TTCP powder was whisker-treated for 5 minutes according to the process described in Example 1. X-ray diffraction (XRD) was performed using an X-ray diffractometer (Rigaku D-max IIIV, Tokyo, Japan) with Ni-filtered CuKα radiation operated at 30 kV and 20 mA at a scanning speed of 1°/min. The phases were identified by matching each characteristic XRD peak with that compiled in JCPDS files.

Results: As indicated in FIG. 2, the XRD pattern of the whisker-treated TTCP powder (b) is substantially identical to that of TTCP as synthesized (a). The perfect match of every XRD peak position (diffraction angle) with the JCPDS data indicates that there is no additional phase formed during the whisker treatment. 0.7 g whisker-treated TTCP powder with 0.25 ml setting solution to form a CPC paste. The setting solution was prepared by dissolving 20 g (NH₄)₂HPO₄ in 40 ml deionized water. The CPC paste was filled in a cylindrical mold (12 mm in height and 6 mm in diameter), allowing hardening of the paste to occur within the mold. After 15 minutes the hardened CPC sample was removed from the mold and immersed in a 37° C. Hanks' solution for 24 hours. After removing from the Hanks' solution and drying, the CPC sample was ready for XRD analysis. After immersion in Hanks' solution for 24 hours, the XRD pattern (c) of the CPC shows a large amount of HA phase which has replaced TTCP as the dominant phase. At this time only a small amount of TTCP remains. The result suggests that the CPC prepared from the whisker-treated TTCP powder of the invention can quickly transform into HA (the major component of human bone), once implanted.

EXAMPLE 10 Setting Solution Prepared from (NH₄)H₂PO₄ and KOH

A TTCP powder was whisker-treated for 5 minutes according to the process described in Example 1. The resulting powder cake was dried in an oven at 50° C. The dried powder was ground for 120 minutes. A setting solution was prepared by dissolving 13.2 g (NH₄)H₂PO₄ in 40 ml deionized water to obtain an initial solution having a pH value of 3.72, and adding KOH to the initial solution so that the pH value was adjusted to 7.5. 100 g of the ground powder and 35 ml of the setting solution were well mixed to form a paste for 1 minute, which was then filled in molds to form specimens for compression tests following the procedures recited in Example 5. Results: compressive strength is 9.6 MPa for the soaking time of 20 min.

EXAMPLE 11 Setting Solution Prepared from (NH₄)H₂PO₄ and NaOH

The procedures in Example 10 were repeated except that the KOH was changed to NaOH and the final pH value of the setting solution was 7.8, and 20 ml of the setting solution was mixed with 100 g of the ground powder. Results: compressive strength is 10.3 MPa for the soaking time of 20 min.

EXAMPLE 12 Setting Solution Prepared from (NH₄)₂HPO₄, NaH₂PO₄.2H₂O and K₂HPO₄

A TTCP powder was prepared following the procedures recited in Example 10. A setting solution was prepared by dissolving 7.5 g (NH₄)₂HPO₄, 2.5 g NaH₂PO₄.2H₂O and 5 g K₂HPO₄ in 40 ml deionized water. The final pH value of the setting solution was 7.56. 100 g of the ground powder and 30 ml of the setting solution were well mixed to form a paste for 1 minute, which was then filled in molds to form specimens for compression tests following the procedures recited in Example 5. Results: compressive strength is 18.0 MPa for the soaking time of 20 min.

EXAMPLE 13 Setting Solution Prepared from Na₂HPO₄.12H₂O, NaH₂PO₄.2H₂O and (NH₄)₂HPO₄

A TTCP powder was prepared following the procedures recited in Example 10. A setting solution was prepared by dissolving 3 g Na₂HPO₄.12H₂0, 3 g NaH₂PO₄.2H₂O and 7.5 g (NH₄)₂HPO₄ in 40 ml deionized water. The final pH value of the setting solution was 7.38. 100 g of the ground powder and 30 ml of the setting solution were well mixed to form a paste for 1 minute, which was then filled in molds to form specimens for compression tests following the procedures recited in Example 5. Results: compressive strength is 20.8 MPa for the soaking time of 20 min.

EXAMPLE 14 Setting Solution Prepared from Phosphoric Acid and Ammonia SOLUTION

A TTCP powder was prepared following the procedures recited in Example 10. A setting solution was prepared by mixing 37.68 ml of 85 wt % phosphoric acid and 100 ml deionized water, and then 73.8 ml of 28 wt % ammonia solution. The final pH value of the setting solution was 7.0. 100 g of the ground powder and 30 ml of the setting solution were well mixed to form a paste for 1 minute, which was then filled in molds to form specimens for compression tests following the procedures recited in Example 5. Results: compressive strength is 23.4 MPa for the soaking time of 20 min.

Although a “basic” whisker can be grown on TTCP surface by immersion in a variety of solutions, the process should be carefully controlled. For example, when the solution contains a P source in the absence of Ca, the immersion time should be long enough to grow a basic whisker (an “acidic” whisker is grown at the early stage due to the excess P ions in the solution). Yet the immersion time should not be too long either to avoid the basic whisker's growing too large, that can largely deteriorate the CPC properties.

On the other hand, when the solution does not contain P (e.g., HCl), acidic whisker is never grown on the surface of TTCP particles. All the observed whiskers on TTCP particles at all stages are basic in nature.

In addition to Ca/P ratio, the growth rate of a basic whisker is also sensitive to such process parameters as the type, pH, temperature and ion concentrations of the solution, to name a few.

Although the present invention has been described with reference to specific details of certain embodiments thereof, it is not intended that such details should be regarded as limitations upon the scope of the invention except as and to the extent that they are included in the accompanying claims. Many modifications and variations are possible in light of the above disclosure. 

1-18. (canceled)
 19. A method of making a calcium phosphate cement article comprising: forming a paste by contacting tetracalcium phosphate (TTCP) particles with a setting solution, wherein at least a portion of the tetracalcium phosphate particles have whiskers comprising basic calcium phosphate crystals on the surface of the particles; placing the paste in a form; and allowing the paste to at least partially harden in the form.
 20. The method of claim 19, wherein the compressive strength of the hardened calcium phosphate cement article is between about 18.6 MPa to about 48.8 MPa.
 21. The method of claim 19, wherein the basic calcium phosphate crystals on the surface of the TTCP particles are formed by contacting the TTCP particles with a whisker-inducing solution.
 22. The method of claim 21, wherein the TTCP particles are contacted with the whisker-inducing solution for a period of time ranging from about 30 seconds to about 24 hours.
 23. The method of claim 21, wherein the whisker-inducing solution comprises an acid.
 24. The method of claim 21, wherein the whisker-inducing solution comprises a base.
 25. The method of claim 21, wherein the whisker-inducing solution comprises an organic solvent.
 26. The method of claim 21, wherein the whisker-inducing solution comprises substantially pure water.
 27. The method of claim 21, further comprising substantially separating the TTCP particles from the whisker inducing solution after the period of time has elapsed.
 28. The method of claim 27, further comprising heating the separated TTCP particles to a temperature of at least about 50° C.
 29. The method of claim 19, wherein the ratio of TTCP particles to setting liquid is at least about 2.8 g/ml.
 30. The method of claim 19, wherein the Ca/P molar ratio of the calcium phosphate crystals on the surface of the particles is greater than about 1.33.
 31. The method of claim 19, wherein the basic calcium phosphate whiskers have dimensions that are up to about 5000 nm long and up to about 500 nm wide.
 32. The method of claim 19, further comprising contacting the at least partially hardened calcium phosphate cement article with an aqueous solution.
 33. The method of claim 32, wherein the aqueous solution is a physiologically neutral solution.
 34. The method of claim 32, wherein the at least partially hardened calcium phosphate article is contacted with the aqueous solution for a period of time ranging from about 20 minutes to about 24 hours.
 35. The method of claim 32, wherein the aqueous solution comprises Hank's solution.
 36. The method of claim 19, wherein the setting solution comprises a basic solution.
 37. The method of claim 19, wherein the setting solution comprises phosphate ions.
 38. The method of claim 19, wherein the setting solution comprises (NH₄)₂HPO₄.
 39. The method of claim 19, wherein the XRD profile of the hardened calcium phosphate cement articles substantially resembles that shown in FIG. 2 c. 